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Stable crystals of pyrrole compoundRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai)Stable crystals of pyrrole compound description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20050261161, Stable crystals of pyrrole compound. Brief Patent Description - Full Patent Description - Patent Application Claims
TECHNICAL FIELD [0001] The present invention relates to a crystal of 2-amino-3-cyano-4-methyl-5-(2-fluorophenyl)pyrrole, which is useful for the treatment of pollakiuria or urinary incontinence. BACKGROUND ART [0002] WO96/40634 describes that 2-amino-3-cyano-4-methyl-5-(2-fluoropheny- l)pyrrole (hereinafter referred to as the pyrrole compound) has excellent urinary bladder capacity increasing activity and is useful for the treatment of pollakiuria or urinary incontinence. Also Examples 5-(1) and 5-(2) of the above publication describe that crystal (hereinafter referred to as type-II crystal) of the pyrrole compound by recrystallizing the pyrrole compound from a mixed solvent (1:1) of benzene and n-hexane, or benzene. DISCLOSURE OF THE INVENTION [0003] It is necessary to provide drugs having high quality and the same quality so that fixed actions and effects can be ordinary expected. Therefore, there can be required, as an active ingredient of drugs, those which show fixed properties and also have high stability and a form having excellent shelf life. [0004] Also with respect to the pyrrole compound mentioned above, it has been required to find those which show fixed properties suited for the manufacture of drugs and also have a stable form. [0005] Type-II crystal had such a problem that the quality deteriorates in a grinding step in the manufacture of a pharmaceutical preparation because of poor stability. [0006] The inventors of the present invention have intensively studied for the purpose of obtaining a crystal which is stable in the grinding step and can be practically used in the manufacture of a pharmaceutical preparation. [0007] As a result, they have found a crystal which is more stable than conventional type-II crystal (hereinafter referred to as type-I crystal), and thus the present invention has been completed. [0008] Namely, the present invention provides stable type-I crystal of the pyrrole compound. Type-I crystal is characterized by showing diffraction peaks at diffraction angles (2.theta..+-.0.2 degree) of 10.3 degree, 14.3 degree, 15.5 degree, 15.9 degree, 25.1 degree and 25.7 degree in a powder X-ray diffraction spectrum. Among the peaks, peaks at 10.3 degree, 14.3 degree, 15.9 degree and 25.7 degree are more characteristic. [0009] Also type-I crystal is characterized by showing absorption peaks at wavenumbers (cm.sup.-1, .+-.0.2%) of 3373, 3322, 2201, 762, 687 and 640 in an infrared absorption spectrum (KBr method). [0010] Type-I crystal of the present invention can be obtained by recrystallizing in the following manner. [0011] (1) Dissolution Step [0012] The pyrrole compound is dissolved in an organic solvent by heating. As the organic solvent, aromatic hydrocarbon solvents such as toluene, xylene and ethylbenzene are preferable, and toluene is particularly preferable. The amount of the organic solvent is preferably 20 to 40 times by weight, more preferably 20 to 30 times by weight, and particularly preferably 22 times by weight, larger than that of the pyrrole compound. The heating temperature varies depending on the kind and amount of the organic solvent, but is preferably from 60 to 80.degree. C., and particularly preferably about 75.degree. C. This step is preferably carried out in a flow of an inert gas such as nitrogen or argon. [0013] The pyrrole compound to be used can be produced by the method described in Example 5-(1) or Example 5-(2) on pages 43-44 of WO96/40634 and is preferably subjected to an active carbon treatment in advance. The pyrrole compound may be in any crystalline or amorphous form. [0014] To remove insolubles, the solution may be filtered. To prevent the precipitation of crystals during the filtration, filtration is preferably carried out under pressure using a funnel equipped with a heating device. In case the precipitation of crystals is observed in the filtrate, the filtrate is dissolved again by reheating after the filtration. [0015] (2) Cooling Step [0016] The solution is cooled to precipitate crystals. This step is preferably carried out in a flow of an inert gas such as nitrogen or argon using a crystallizer equipped with a heating function for dissolving the precipitate and a stirring function for cooling. [0017] The cooling temperature is preferably from 2 to 20.degree. C., and particularly preferably from 5 to 10.degree. C. After reaching the cooling temperature, the crystallization time is preferably from 30 minutes to 2 hours, and particularly preferably 1 hour. When the solution is cooled to a temperature ranging from 60 to 65.degree. C., type-I seed crystal is preferably added. Type-I seed crystal can be obtained, for example, by operating as described in Example 1 described hereinafter. The amount of type-I seed crystal is preferably from 0.3 to 1.0% by weight based on the pyrrole compound used. The cooling rate is preferably from 0.5 to 1.5.degree. C./min. in case of adding type-I seed crystal, while the cooling rate is preferably 0.5.degree. C./min. in case of adding no type-I seed crystal. [0018] (3) Crystal Collection and Drying Step [0019] The precipitated crystals are collected by a known means such as filtration or centrifugation and then dried. Drying can be carried out under reduced pressure or over a desiccant. Particularly, drying is preferably carried out under reduced pressure, for example, of 10 mmHg or less at 20 to 60.degree. C. for 1 to 48 hours. [0020] As shown in Examples and Test Examples described hereinafter, type-I crystal of the present invention is stable in grinding test as compared with type-II crystal as conventional crystal, and also has good appearance under an electron microscope. Therefore, type-I crystal of the present invention can be advantageously used as a pharmaceutical bulk in the manufacture of a pharmaceutical preparation. BRIEF DESCRIPTION OF THE DRAWINGS Continue reading about Stable crystals of pyrrole compound... Full patent description for Stable crystals of pyrrole compound Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Stable crystals of pyrrole compound patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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